Anyway, welcome to day 4 of Back to Basics week! Today, we're going to look at DOPAMINE and the lovely things we study which involve it. You know, stuff like cocaine. Fun stuff. It's almost Friday!

As you might be able to tell from manyofmyolder and newer posts, I like dopamine. It's one of the transmitters I'm working on for my thesis, in fact. I've talked a little bit about dopamine as it relates to the stuff I blog about, but below I'm going to talk about it a little more. And of course, there's always wikipedia, but I don't really like the ways theirs is organized. Could I edit it? Sure I could. But I've got this laziness problem...

The major problem with trying to do a general post about dopamine is that there is so much out there on it. There's a ton of research going on on dopamine, including Parkinson's Disease, schizophrenia, obsessive compulsive disorder, attention deficit hyperactivity disorder, sleep cycles, and drug addiction, just to name a few. So I'm not going to get to everything there is about dopamine. I'll do my best just to give you the basics on where it comes from, where it goes, and some of the things it does, and though I can by no means cover everything, I will give it my best shot.

It's what we call a monoamine, which basically means it has one amine group (the bit with the blue ball on it, the blue ball is Nitrogen) as part of its structure. There are several monoamines in the brain, including dopamine itself, norepinephrine, and epinephrine. Your brain makes dopamine all the time, out of tyrosine molecules, which are one of the 20 major amino acids that you have that make up all the different proteins and things in your body. Knowing exactly how dopamine is made is actually pretty important, scientists tweak the dopamine pathway all the time to run experiments or treat disease symptoms.

Basically, tyrosine (your starting molecule) is transformed into another chemical called L-DOPA by an enzyme known as tyrosine hydroxylase. Tyrosine hydroxylase is the rate limiting step (basically, the slowest one) in the formation of dopamine, and so scientists often manipulate levels of tyrosine hydroxylase in animals to look at the effects on dopamine levels in the brain. You can also look at levels of tyrosine hydroxylase to see how much dopamine there is likely to be at any given time.

So tyrosine hydroxylase makes L-DOPA. L-DOPA is the molecule right before dopamine and is very well known as the drug Levodopa. This is the main treatment for Parkinson's Disease. See, the issue with dopamine is that it gets broken down in the body VERY quickly, and so if you take it as a pill or something, it would never get to the brain and help your symptoms. L-DOPA, however, doesn't get broken down in the body, instead it goes to the brain and is broken down there into dopamine, which is why you can take L-DOPA as a pill and get dopamine into your brain. L-DOPA is changed into dopamine via an enzyme known as aromatic amino acid decarboxylase (AADC), and then you have dopamine, ready to be stored and released as either a neurotransmitter or a hormone.

Dopamine the Neurotransmitter

For those of you who've been hearing me say "neurotransmitter" for the past few months and keep going "wha?", a neurotransmitter is a chemical signalling molecule in the brain. As I'm sure you know, brains are made of cells, and cells have to communicate with one another. They do this by sending signals. Within a cell, the signals move as electical waves along the cell membrane (called action potentials), but when it comes to signalling to another cell, they have to do something else. It's not considered polite to just go zapping your neighbor. So when a signal gets to the synapse (the junction where two cells meet), the signal is translated into a release of chemical from one cell (the presynaptic cell) to the other (the post-synaptic cell). I looked around on youtube, and one of the best videos I could find of this was here.

Though this is also awfully good, and includes a bit about why I blog about dopamine specifically:

When a neurotransmitter is released into a synapse, it crosses the tiny gap and binds to receptors specifically for it on the other side. In dopamine's case, we call these receptors D1, D2, D3, D4, and D5, which are just numbers assigned to the receptors with specific sequences in their protein structure. The receptor activation goes on to produce either a further action potential or to inhibit signalling, depending on the kind of cell and the receptor involved.

So we know now that dopamine is a signalling molecule. But not every cell has dopamine, and in fact dopamine is produced only in a few, very specific regions of the brain. The regions that I am concerned with are the Substantia Nigra and the Ventral Tegmental Area. The substantia nigra (latin for black substance) actually IS black. It looks like someone has been drawing little pencil lines near the base of your brain. The cells themselves are black because they contain high levels of melanin, which makes things very dark in appearance. The substantia nigra is located in an area of the brain called the midbrain. I guess this is the best picture for getting an idea of exactly where that is...

From Wikipedia.

I really wish I had a fresh brain slice to show you. It looks so cool when you can see it in the midbrain right above the peduncles...

The substantia nigra is one of the main places in the brain which modulates (changes or affects) movement. It is famous for the degredation that takes place there to produce the symptoms of Parkinson's Disease, which include tremor, akinesia (an inability to move), and rigidity.

In that picture, you can also see the Ventral Tegmental Area, which we like to call the VTA. It's an area ths is right next to the substantia nigra, and one that I tend to like to blog about more. the VTA projects forward toward an area known as the striatum, and particularly to an area I like very much, the Nucleus Accumbens. This is an area of the brain which we think is very concerned with the concepts of motivation and the rewarding aspects of stimuli (it always amuses me that "stimuli" is basically the science term for "stuff"). Dopamine, which is sometimes known as the "pleasure molecule", increases in the nucleus accumbens when we get things that are "rewarding", such as sex, drugs (especially drugs), rock and roll, food, chocolate, pretty shoes, etc. Changes in dopamine signalling in the nucleus accumbens are thought to be linked to things like addiction. Of course, dopamine also goes other places, including the prefrontal cortex, which is thought to have a role in schizophrenia, ADHD, and obsessive compulsive disorder.

Dopamine as a Hormone

Dopamine also acts as a hormone which has its main effects in the hypothalamus. Here, release of dopamine inhibits the secretion of prolactin. Prolactin is a hormone which helps regulate orgasm and the release of milk during breast feeding. I don't tend to blog about this stuff so much, though the dopaminergic regulation of the refractory period after orgasm is pretty cool.

Dopamine Receptors and Transporters

A lot of research on dopamine signally focuses on the receptors and transporters involved. Luckily, there aren't very many actual receptors and there's only one transporter (though it comes in two different flavors), though between them they can have dizzying arrays of effects.

The dopamine transporter (DAT)

The DAT is a big molecule found on the pre-synaptic side of a synapse. It's dopamine's recycler. Dopamine needs to be released in sharp bursts, you don't want a signal hanging around and stimulating forever, so once dopamine is in the synapse, it is very quickly recycled by the DAT back up into the pre-synaptic cell, where it can be re-stored and used again. There are technically two kinds of DAT, DAT1 and DAT2, but most drugs don't differentiate, and so most things I'll talk about treat them as one.

The DAT is mostly well known because people believe that it is responsible for some of the effects of cocaine. Cocaine is a molecule that blocks the DAT, so dopamine cannot get recycled. Instead, it builds up in the synapse, stimulating the post-synaptic neuron over and over again, and causing lots of motor movement, focus, and euphoria. There are lots of other molecules out there which affect the DAT, including amphetamine (also know as Adderall), methylphenidate (also known as Ritalin, and while I must blog about extensively some day), methamphetamine (SCARY), and possibly even some of the effects of alcohol. Other drugs of abuse may not act directly on the DAT, but still have effects on the dopamine system, such as morphine, percoset, nicotine, and marijuana.

Dopamine receptors

There are five dopamine receptors, and luckily they all act in one of two ways! Unluckily, that does not make them at all less complicated.

DA D1 and DA D5: These are known as "stimulatory receptors", meaning they stimulate the cell that they are on when they get activated by dopamine. Now, if that cell is ALSO stimulatory to further cells down the line, the net effect is stimulation, but if the cell is inhibitory to other cells down the line, the net effect can be inhibition.

DA D2, D3, and D4: These are known as "inhibitory" receptors. But remember the main effect is not always inhibitory, unless they are inhibiting a stimulatory cell. They can also inhibit an inhibitory cell, which can stop inhibition of other cells down the like and result in stimulation! Does your head hurt yet?

There are lots of drugs out there (usually only used in experimental settings) which activate one or more of these receptors, so that we can see what the effects of any given receptor in any area of the brain are, though we still don't know half of all there is to know about these receptors.
That's where I'm going to leave the subject of dopamine right now. Believe me, you have no idea (I also have no idea) how deep the rabbit hole goes. But this should be enough to give you an idea of what dopamine is when I talk about it, and a little about how it works.

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[...] cocaine. Previous studies in the Zahniser lab have shown that these LCR rats have higher numbers of dopamine transporters. Dopamine is a neurotransmitter which is associated with feelings of reward/motivation [...]

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